HIV/AIDS afflicts 33 million people and a preventive vaccine that will stop transmission of HIV is desperately needed. We will engineer the pioneer Streptococcus mitis oral bacterium to create a safe and effective recombinant vaccine vector against infant and adult AIDS. The S. mitis-based vaccine strategy will have the unique features of the pioneer bacterium that will make this strategy effective against mucosal transmission of HIV. The recombinant S. mitis vector will be safe and capable of colonizing the oral cavity and nasopharynx of infants and adults abundantly and persistently to elicit robust mucosal immunity. In this study, we will develop the first preclinical small animal model of S. mitis colonization to evaluate the potential usefulness of the S. mitis-based vaccine strategy for the prevention of AIDS. The recombinant S. mitis will be engineered to express HIV/SIV antigens with different localization signals and subsequent preclinical immunogenicity testing will be conducted to assess whether recombinant S. mitis will induce mucosal immunity in the oral cavity, gut and vagina, which are the primary portals of entry and replication for the AIDS virus. These studies are a critical step towards developing recombinant S. mitis as a potential candidate vaccine vector against pediatric and adult AIDS and other diseases. PUBLIC HEALTH RELEVANCE: HIV/AIDS is a major global public health problem that needs an immediate solution. We propose to develop an innovative and novel recombinant Streptococcus mitis vaccine technology against HIV and other debilitating diseases.